: In the U.S., infection is a leading cause of death among patients with chronic renal failure (CRF). This is due in part to the immune deficiency of the uremic syndrome. In the past decade, apoptosis or programmed cell death (PCD) has been the subject of intense investigation. In contrast to necrosis, apoptosis is a programmed, active and highly selective death mechanism, allowing for the removal of redundant or excessively damaged cells. It is an essential component of development and cellular regulation, and in both excessive and reduced amount, has pathophysiological and therapeutic implications. In CRF, polymorphonuclear leukocytes (PMN) undergo accelerated PCD. The long-term goals of this proposal are to elucidate the cellular and molecular pathways governing PMN apoptosis in CRF. The studies will specifically concentrate on three major signaling pathways: the Fas/FasL system, the Bax/Bc12 system and oxidative stress. The studies will utilize PMN (healthy subjects and patients with CRF) and HL-60 granulocytes. Apoptosis induction models will use receptor- and stress-mediated stimuli (anti-Fas antibodies, pro-oxidant agents, dialysis membranes, uremic toxins, etc). The results are expected to enhance our understanding of leukocyte biology in CRF, and lay the foundation for developing novel strategies to combat immune dysfunction in CRF.